Acepromazine inhibits hERG potassium ion channels expressed in human embryonic kidney 293 cells

Abstract

The effects of acepromazine on human ether-à-go-go-related gene (hERG) potassium channels were investigated using whole-cell voltage-clamp technique in human embryonic kidney (HEK293) cells transfected with hERG. The hERG currents were recorded with or without acepromazine, and the steady-state and peak tail currents were analyzed for the evaluating the drug effects. Acepromazine inhibited the hERG currents in a concentration-dependent manner with an IC50 value of 1.5 µM and Hill coefficient of 1.1. Acepromazine blocked hERG currents in a voltage-dependent manner between –40 and +10 mV. Before and after application of acepromazine, the half activation potentials of hERG currents changed to hyperpolarizing direction. Acepromazine blocked both the steady-state hERG currents by depolarizing pulse and the peak tail currents by repolarizing pulse; however, the extent of blocking by acepromazine in the repolarizing pulse was more profound than that in the depolarizing pulse, indicating that acepromazine has a high affinity for the open state of the channels, with a relatively lower affinity for the closed state of hERG channels. A fast application of acepromazine during the tail currents inhibited the open state of hERG channels in a concentration-dependent. The steady-state inactivation of hERG currents shifted to the hyperpolarized direction by acepromazine. These results suggest that acepromazine inhibits the hERG channels probably by an open- and inactivated-channel blocking mechanism. Regarding to the fact that the hERG channels are the potential target of drug-induced long QT syndrome, our results suggest that acepromazine can possibly induce a cardiac arrhythmia through the inhibition of hERG channels.

Comparison of the effects of propofol and alfaxalone on the electrocardiogram of dogs, with particular reference to QT interval

“…It is also possible that acepromazine may have played a role. An experimental study in humans reported that acepromazine may have a potentially arrhythmogenic action through the inhibition of human ether-à-go-go-related gene (hERG) potassium channels in cardiac tissues and the prolongation of QT intervals ( 61 ). We elected to use methadone as premedication in the dogs in this study as it is the only full opioid agonist currently licensed in this species in the U.K. and Europe, and we wanted to produce data relevant to clinical veterinary practice.…”